X - Radiological Society of North America



X. Imaging Protocol

0. Executive Summary

Provide a brief (less than 250 words) synopsis to let readers quickly determine if this imaging protocol is relevant to them. Sketch key details such as the primary utility, imaging study design, specific aims, context, methods, expected results, risks, and deliverables.

EU - The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out, interpret, and document quantitative FDG PET/CT examinations, but will concentrate on the optimisation of diagnostic quality and quantitative information.

Netherlands - This imaging protocol defines the standard of quantitative FDG whole body PET performed in the Netherlands, officially approved by the Dutch Society of Nuclear Medicine since 09November2007. The aim is to ensure that multi-center FDG-PET studies using SUV (standardized uptake value) measurements are conducted in a standardized manner. With the aim to minimize intersubject and inter-institute variability of SUV measures, factors affecting SUV outcomes are reviewed, guidelines and recommendations are described and limitations, pending issues and future work are discussed.

Hallett - As FDG-PET imaging data are currently being used to support internal decision making in drug development, and ultimately may be used to support registration, the data need to be easily acquired, quality controlled and analyzed, with high fidelity. Moreover, qualification of an imaging parameter as a surrogate endpoint will require

standardization of the original imaging data or derived values to support metaanalyses

of several d rug trials, and possibly over different compounds and different companies.

NCI - Despite the increasing use of 18F-FDG PET as a biomarker for predicting therapeutic response, there are no widely accepted standardized protocols for using 18F-FDG PET as a tool for assessing response to therapy, nor are there validated criteria for judging response using 18F-FDG PET.

Enacting these recommendations to develop standard protocols for NCI-sponsored clinical trials should go a long way toward determining when and for what indications 18F-FDG PET can serve as a surrogate measure of therapeutic efficacy.

ACRIN 6665:

Metabolic changes in the tumor in response to Gleevec therapy, as defined by PET and FDG- PET, appear to occur very rapidly, and may precede significant changes in size as defined by conventional anatomic modalities. Therefore, non-invasive imaging studies that allow measurement of regional tumor metabolism on the in-situ tumor prior to and during the drug administration could provide useful information regarding assessment of therapeutic response. Glucose transporters play a major role in FDG uptake and GLUT 4 is overexpressed in gastrointestinal tumors. (Nogushi Y, et. al., Expression of glucose transporters and insulin resistance in human GI cancer. Abstract, Proc. Annual Mtg., AACR 36:A1218, 1995) Hence, the availability of tissue pre and post therapy will help elucidate the relationship between FDG uptake and glucose transporter expression in GIST at baseline, and after therapy.

ACRIN 6671:

The primary objective of this study is to evaluate the diagnostic sensitivity and specificity of FDG-PET/CT imaging in identifying metastases to abdominal (common iliac, para-aortic, and para-caval) lymph nodes in patients with cervical cancer (stages IB2, IIA ≥4 CM, IIB-IVA) and abdominal (common iliac, para-aortic, and para-caval) and pelvic lymph nodes in patients endometrial cancer (Grade 3 endometrioid or non-endometrioid endometrial carcinoma, any grade carcinosarcom, or Grade 1 or 2 with cervical involvement). The diagnostic sensitivity and specificity of FDG-PET/CT will be evaluated in a central reader study including seven (7) expert readers.

ACRIN 6678:

Background: Several studies have suggested that positron emission tomography (PET) with the glucose analog fluorodeoxyglucose (FDG) may be used to monitor tumor response very early in the course of therapy for NSCLC. However, further validation is necessary before FDG-PET can be used as a new marker for tumor response in clinical trials or for the management of individual patients.

Aim: The trial aim is to show that quantitative changes in FDG uptake during chemotherapy provide an early readout for the effectiveness of therapy in patients with advanced non-small cell lung cancer (NSCLC).

Hypotheses: The two hypotheses underlying this trial are that (i) a metabolic response, defined as a 25% or greater decrease in peak tumor SUV post-cycle 1 of chemotherapy, provides early prediction of treatment outcome (tumor response and patient survival) and (ii) tumor glucose utilization can be measured by FDG-PET with high reproducibility.

Endpoints: The primary endpoint of this study is the prediction of one-year overall survival by monitoring the metabolic response of the tumor following one cycle of chemotherapy. Secondary endpoints are (i) the correlation between a metabolic response after one cycle of chemotherapy and subsequent best tumor response according to standard anatomic response using the RECIST evaluation criteria, (ii) correlation between a metabolic response after the first chemotherapy cycle and progression- free survival, (iii) a comparison of the predictive value of FDG-PET for one-year overall survival after one and two cycles of chemotherapy, (iv) the test-retest reproducibility of standardized uptake values (SUVs).

ACRIN 6685:

The advent of positron emission tomography (PET) has improved the staging, treatment evaluation, and detection of recurrent disease in patients with head and neck SCC. With added anatomical information from CT, PET/CT has demonstrated the ability to identify metastatic head and neck malignancies in cases where the other imaging techniques have failed. Several studies have evaluated fluorodeoxyglucose (FDG)-PET in this setting, attempting to identify the patients who need radical neck dissection. A large scale clinical trial that shows accurate characterization of disease stage will impact treatment success by potentially identifying true N0 necks without invasive therapeutic treatment and subsequent morbidity while recognizing the most appropriate clinical management.

In this study, participants with newly diagnosed head and neck SCC will undergo a FDG-PET/CT scan prior to surgical resection. The surgeon will have access to the FDG-PET/CT results prior to the surgical procedure. The data will demonstrate how the inclusion of the FDG-PET/CT imaging will impact the determination of extent of disease, disease characterization and prognosis, and the surgical plan originally devised from clinical nodal assessment and CT and/or MRI results. Quality of life (QoL) assessments and cost effectiveness analysis (CEA) will be included in the study to determine the impact of FDG-PET/CT inclusion relative to surgical assessment of the N0 neck. QoL results will be used to evaluate reduction in morbidity associated with potentially more-definitive targeting of metastatic disease; CEA analysis targets potential reductions in costs from identifying a truly N0 neck and reducing need for therapeutic dissection, follow up, subsequent re-dissection from missed disease, etc. Prior to imaging, blood samples will be collected to explore serum biomarkers as they correspond to prognosis, staging, and FDG-PET/CT findings. Future correlation between blood and imaging biomarkers may strengthen clinical confidence in defining the N0 neck. Ultimately, the study may show that FDG- PET/CT images will improve the characterization of the N0 neck by accurately diagnosing N0 necks, better defining extent of primary disease, discovering unappreciated distant metastasis, reducing morbidity, and representing cost-effective value to society.

1. Context of the Imaging Protocol within the Clinical Trial

Describe how this imaging protocol interfaces with the rest of the clinical trial.

1. Utilities and Endpoints of the Imaging Protocol

Describe one or more utilities or endpoints this Imaging Protocol could serve in a Clinical Trial.

(e.g. to determine eligibility of potential subjects in the clinical trial; to triage eligible subjects into cohorts based on stage or severity of disease; to assess response to treatment; to establish the presence of progression for determining TTP, PFS, etc.; to monitor for adverse events; to establish a database for the development, optimization, and validation of imaging biomarkers, etc.)

Common standards will help promote the use of PET/CT imaging and increase the value of publications and their contribution to evidence-based medicine and potentially enable the role of semi-quantitative and quantitative image interpretation since the numeric values should be consistent between platforms and institutes that acquire the data. FDG PET/CT is being used increasingly to evaluate tumour response in addition to diagnosis and staging of tumours. Increasingly, research is being performed in radiotherapy planning and it will be important that areas such as edge detection of tumours have a translatable measurement.

Integrated PET/CT combines PET and CT in a single imaging device and allows morphological and functional imaging to be carried out in a single imaging procedure. Integrated PET/CT has been shown to be more accurate for lesion localisation and characterization than PET and CT alone or the results obtained from PET and CT separately and interpreted side by side or following software based fusion of the PET and CT datasets. PET/CT gains more and more importance in oncology imaging. At the same time, there is greater awareness that the quantitative features of PET may have a major impact in oncology trials and clinical practice. Therefore this guideline focuses on the use of FDG PET/CT in oncology.

Show the usefulness of FDG-PET quantification using SUV’s for diagnosis and staging, prognostic stratification and monitoring treatment response in multicenter oncology clinical trials.

By standardizing FDG-PET trial design and interpretation the field will contribute to

increased efficiency and precision of its application to decision making in drug

development. In this publication we highlight areas, especially in image analysis

and response classification, that are currently in need of expert guidance and in

some instances further research. While the benefits for treatment planning are clear,

perhaps less obvious are the profound implications for the development of new

tumor agents. Early detection of drug response can significantly reduce the time

required to conduct proof-of-concept studies for new drug candidates and FDG

metabolism may offer a sensitive means of defining the clinical dose range. Moreover, FDG-PET can be used as a translational method; that is, used in

animal models for testing lead candidates for new treatments.

We intend that it (this document) serve as the recommended set of procedures for the acquisition and analysis of 18F-FDG PET scans of patients participating in NCI-sponsored

diagnostic and therapeutic clinical trials. We hope that these guidelines will help bring about a future in which 18F-FDG PET can provide an early metabolic assessment of therapeutic response.

ACRIN 6665:

Biological Objectives:

1) Correlation of glucose transporter expression with PET SUV and TBR pre-and post Gleevec neoadjuvant therapy.

Clinical Objectives:

1) Measure tumor changes by PET qualitatively and semi-quantitatively with SUV and TBR during the first week of neoadjuvant treatment and prior to surgery (at week 4 in patients with progressive disease, at week 8 to 10 in patients with stable or responding disease), and correlate the findings with size changes as defined by conventional cross-sectional imaging scans. PET scanning is mandatory for all patients. PET scans may be obtained at affiliated, accredited institutions if the institution enrolling the patients does not have such capability.

2) Determine if the percent decline in SUV and TBR is an earlier, or more accurate predictor of subsequent disease recurrence compared with response assessed by conventional cross-sectional imaging scans.

ACRIN 6671:

Primary Objectives

1) To evaluate the diagnostic sensitivity and specificity of preoperative FDG-PET/CT imaging in identifying metastases to abdominal (common iliac, para- aortic, and para-caval) lymph nodes in participants with locoregionally advanced cervical carcinoma.

2) To evaluate the diagnostic sensitivity and specificity of preoperative FDG- PET/CT imaging in identifying metastases to retroperitoneal abdominal lymph nodes in participants with high-risk endometrial cancer.

Secondary Objectives

1) To evaluate the diagnostic sensitivity and specificity of preoperative FDG-

PET/CT imaging in identifying metastases to pelvic lymph nodes (obturator, external iliac) and pelvic and abdominal lymph nodes combined in participants with locoregionally advanced cervical carcinoma.

2) To evaluate the diagnostic sensitivity and specificity of preoperative FDG- PET/CT imaging in identifying metastases to pelvic lymph nodes and pelvic and abdominal lymph nodes combined in participants with high-risk endometrial cancer.

3) To evaluate the additive diagnostic value of CT fusion (PET/CT) compared with PET scanning alone in the identification of metastases to pelvic (obturator, external iliac), abdominal (common iliac, para-aortic, and para-caval), and combined (all regions) lymph nodes in participants with locoregionally advanced cervical carcinoma or high-risk endometrial carcinoma.

4) To determine the percentage of participants with locoregionally advanced cervical carcinoma or high-risk endometrial cancer in whom PET/CT detects biopsy- proven disease outside the abdominal or pelvic lymph nodes.

5) To evaluate the diagnostic sensitivity and specificity of PET/CT in the identification of metastases to pelvic (obturator, external iliac), abdominal (common iliac, para-aortic, and para-caval), and combined (all regions) lymph nodes in a combination of locoregionally advanced cervical cancer and high-risk

The primary metrics of diagnostic accuracy for all of the above will be sensitivity and specificity. The reference standard is the result of pathological evaluation of pelvic and abdominal lymph nodes. Objectives will be evaluated primarily through central reader studies.

ACRIN 6678:

This study has four objectives:

1.) To test whether a metabolic response, defined as a ≥ 25% decrease in peak tumor SUV post-cycle 1 of chemotherapy, provides early prediction of treatment outcome (tumor response and patient survival).

2.) To determine the test-retest reproducibility of quantitative assessment of tumor FDG uptake by SUVs.

3.) To study the time course of treatment-induced changes in tumor FDG uptake.

4.) To evaluate in an exploratory analysis changes in tumor volume during chemotherapy by multislice CT.

The two specific hypotheses underlying this trial are (i) a metabolic response, defined as a ≥ 25% decrease in peak tumor SUV post-cycle 1 of chemotherapy, provides early prediction of treatment outcome (tumor response and patient survival) and (ii) tumor glucose utilization can be measured by FDG-PET/CT with high reproducibility.

Primary Endpoint

The primary endpoint of this study is the prediction of one-year overall survival by monitoring changes in tumor metabolic activity during the first chemotherapy cycle, where metabolic response is classified as ≥ 25% decrease in SUV of the primary tumor relative to baseline (pre-chemotherapy).

Secondary Endpoints

1) Assessment of the association between a metabolic response after one cycle of chemotherapy and subsequent best tumor response according to standard anatomic response evaluation criteria (RECIST).

2) Assessment of the association between a metabolic response after the first chemotherapy cycle and progression-free survival.

3) Assessment of the test-retest reproducibility of SUVs measured by PET/CT systems.

Exploratory Data Analysis

In addition to the specific endpoints described above, the trial provides data for hypothesis-forming analyses. Specifically, the following questions will be addressed:

1) Will the ability of FDG-PET/CT to predict one-year survival be comparable after one and two cycles of chemotherapy?

2) Could ROC analysis be used to estimate an optimal threshold for the SUV differences in defining a metabolic response?

3) Can changes in tumor volume be assessed by multi-detector CT early during the course of chemotherapy?

4) Are tumor volumetric changes correlated with patient outcomes?

5) Can one develop parameters that combine metabolic and volumetric data and do these parameters allow a better prediction of patient outcome than metabolic changes alone?

6) How does the prognostic value of a metabolic response in PET compare with the prognostic value of tumor response according to standard tumor response assessment according to RECIST?

7) What is the correlation between metabolic changes in the primary tumor and in metastatic lesions?

8) How should changes in FDG uptake of multiple metastatic lesions be quantified?

ACRIN 6685:

Primary Endpoint

Determine the negative predictive value (NPV) of PET/CT for staging the N0 neck based upon pathologic sampling of the neck lymph nodes and determine PET/CT’s potential to change treatment of the N0 neck.

3.2 Secondary Endpoints

1) Estimate the sensitivity and diagnostic yield of PET/CT for detecting occult metastasis in the clinically N0 neck (both by neck and lymph node regions) or other local sites;

2) Determine the effect of other factors (eg, tumor size, location, secondary primary tumors, or intensity of FDG uptake) that can lead to identification of patient subsets that could potentially forego neck dissection or provide preliminary data for subsequent studies;

3) Analyze cost-effectiveness of using PET/CT for staging of head and neck cancer versus current good clinical practices;

4) Evaluate the incidence of occult distant body metastasis discovered by whole body PET/CT;

clinicians intend to dissect beyond the initial surgery plan—based on local-reader PET/CT findings shared with the surgeon prior to dissection;

5) Estimate the optimum cutoff value of SUV for diagnostic accuracy of PET/CT test;

6) Evaluate the impact of PET/CT on the N0 neck across different tumor subsites (defined by anatomic location).

7) Correlate PET/CT findings to CT/MRI and biomarker results;

8) Evaluate quality of life, particularly in participants whose patient management could have been altered by imaging results;

9) Evaluate the PET/CT and biomarker data for complementary contributions to metastatic disease prediction;

10) Compare baseline PET/CT and biomarker data to 2-year follow up as an adjunct assessment of their prediction of recurrence, disease-free survival, and overall survival;

11) Determine the proportion of neck dissections that are extended—additional levels

Clinical Implications from the Objectives

1) We will evaluate the potential impact on patient management of PET/CT in staging head and neck cancer. The primary, implied management change will be in treatment of the clinically N0 neck. For example, if PET/CT has a high NPV in the N0 neck, this would imply that observation only of the neck could be entertained.

2) We will assess the potential impact of PET/CT, if found to have high sensitivity for identifying neck disease, to estimate the potential for influencing changes in neck dissection strategies from standard selective neck dissection to standard plus targeted neck dissection or radiotherapy.

3) Newly-identified biomarkers may provide additive predictive ability to PET/CT in the risk assessment of advanced disease/metastasis. We will evaluate the ability of serum biomarkers to predict disease at the time of presentation and in follow up within 2 years.

4) We will be able to estimate the clinical impact of detecting distant metastases using PET/CT.

5) We will be able to estimate the cost-effectiveness of these strategies employed to evaluate N0 neck status.

6) We will assess quality of life among participants, and apply it to those whose clinical strategy could have been adjusted based on information from the PET/CT.

Hypotheses

1) PET/CT can more accurately identify head and neck cancer—or the absence thereof—at primary, nodal, or distant sites than clinical exam, CT, or MRI.

2) This additional PET/CT imaging information will lead to important changes in patient care, patient QoL, costs, and cost-effectiveness, specifically as relate to treatment of the N0 neck.

3) These changes may result from upstaging an N0 neck to N+, better defining extent of primary disease, or uncovering unappreciated distant metastasis.

Other biomarkers may correspond to FDG-PET/CT findings, clinical stage, and patient outcomes. These findings may reflect the aggressiveness of the clinical course, which in turn may direct the patient towards more or less aggressive modality therapy.

2. Timing of Imaging within the Clinical Trial Calendar

Describe for each discrete imaging acquisition the timing that will be considered “on-schedule” preferably as a “window” of acceptable timing relative to other events in the clinical trial calendar. Consider presenting the information as a grid which could be incorporated into the clinical trial calendar.

In clinical trials, the study protocol should define the interval between administration of such substances and the PET study. For clinical practice several recommendations have been published [7] (see also e.g. JNM Supplement 2009). A minimum interval

between the last dose (chemotherapy) and the PET study should be 10 days, if possible, or probably as close to the next treatment administration as possible.

Though there are no conclusive data on the optimum interval between chemotherapy and PET, an interval of at least 10 days is generally considered between the last treatment and PET. This is because of any possible effects on tumour metabolism (such as macrophage impairment) and systemic effects (such as bone marrow activation following bone marrow depression, which may or may not be caused by growth factors). The effects of growth factors (Gm-CSF) or FDG biodistribution (due to enhanced bone marrow uptake) do not last for more than 2 weeks after the final administration.

It is assumed that the effects of radiotherapy are somewhat longer lasting; investigation of cases of laryngeal carcinoma treated by radiation has shown that due to radiation-induced inflammation, it is best to wait for about 3 months after the end of treatment before conducting FDG PET. This timing fits well into this clinical context as these patients rarely develop clinical problems in the first 3 months after treatment.

Intervals between interventions and PET should be specified for each (research) protocol.

For routine clinical care in solid tumours, an interval between the end of last (chemo-) therapy cycle and FDG-PET must be at least 14 days. In case of radiation treatment, an interval up to 4 months may be required occasionally (e.g. larynx carcinoma). For malignant lymphoma therapy evaluation, time intervals have been specified by the Imaging Subcommittee of International Harmonization Project in Lymphoma. -

For response monitoring, the time interval between the baseline FDG-PET study and start of treatment as well as the time intervals between subsequent FDG-PET studies and cycles of treatment are of importance -

Insufficient data are available on the optimal interval from completion of therapy to imaging with 18F-FDG PET. Nevertheless, the working group recommends that the complete

treatment history of the patient be documented, particularly the use of supportive therapies such as bone marrow expansion drugs and the recent use of corticosteroids. Pretreatment

scanning is generally critical to assess subsequent response. The timing of posttreatment scanning depends on numerous variables, including correlative studies, whether a complete

clinical response variable is under consideration, the expected responsiveness of the tumor type to the therapy being used, and the endpoints of the study.

Currently available information supports the recommendation that posttreatment imaging be performed 2 wk after the end of a specific chemotherapy cycle. The exact timing may depend on the frequency and duration of therapy. It is postulated that the transient and nondurable alterations in 18F-FDGuptake that may occur in tumors during the immediate posttreatment

period will be minimized using this approach. A specific understanding of the basic biology of the tumor from previous clinical and preclinical studies may help one determine the optimal posttreatment time point. Data on the treatment interval after the completion of

radiotherapy are less clear. Acute inflammatory changes with subsequent alterations in 18F-FDG uptake in both tumor and surrounding tissue have been documented.

Newer radiation therapies such as g-knife and focal high dose radiation appear to enhance inflammatory reactions, and thus confound the interpretation of 18F-FDG PET scans, in patients studied within a short period after completing these therapies (32). Many investigators recommend a delay of 6-8 wk or longer after radiation therapy before

performing the posttreatment 18F-FDG PET study.

Although further study may be required to arrive at an appropriate interval for scanning after completion of radiation therapy, a longer wait clearly helps in distinguishing

inflammatory response from viable residual tumor.

ACRIN 6665:

PET will need to be performed pre-treatment at baseline, within 24 hours to 1 week following initiation of therapy, and just prior to surgery. PET is performed at 4 weeks in patients with progressive disease or preoperatively.

1) Initial PET scanning within 8 weeks before registration prior to initiation of drug therapy.

2) FDG PET Imaging at Week 1: In addition to the baseline PET scan, an additional PET scan will be obtained shortly after the initiation of therapy, optimally 24 hours following the administration of the first dose of the drug. If not feasible, the scan should be performed during the first week following the start of therapy but no later than day 7. It will be performed using the same technique used for the baseline scan.

3) FDG PET Imaging Before Surgery : The final study will be done just prior to surgery. (It is recommended that whenever possible the study be done in the week prior to surgery). It will be performed using the same technique used for the baseline scan, according to the instructions given in Section 11.6.1. The scan will be read without knowledge of the pathology results obtained after surgery.

3. Management of Pre-enrollment Imaging –

Describe the evaluation, handling and usage of imaging performed prior to enrollment.

Clearly identify purposes for which such imaging may be used: eligibility determination, sample enrichment, stratification, setting the measurement base-line, etc.

(e.g. What characteristics or timing will make the imaging acceptable for the purpose?

Will digitized films be accepted?

Will low-grade images be annotated and/or excluded from parts of the trial?

Is there normalization that should be done to improve low-grade priors?

How should such imaging be obtained, archived, transferred, etc.)

ACRIN 6665:

CT or MRI Scans for disease assessment within 8 weeks prior to registration. All disease assessment must be performed using the same assessment technique (either CT or MRI).

Initial PET scanning within 8 weeks before registration prior to initiation of drug therapy.

ACRIN 6671:

ACRIN 6678:

If a pre-enrollment baseline scan was performed on a platform that is not ACRIN-qualified or does not meet the other trial requirements, the baseline scan should be repeated within the trial budget. Images acquired on ACRIN-qualified platform prior to registration meeting all other trial requirements (including, but not limited to, the trial-specified time window) could be used as the baseline exam. The exam will still be subjected to trial imaging exam QA.

ACRIN 6678:

If the first FDG-PET/CT scan may be completed prior to registration if: a) the PET/CT scanner has been qualified for the 6678 protocol; b) all parameters and scanning techniques are completed per protocol guidelines; and c) all subsequent PET/CT scans are performed on the same scanner or the same scanner model.

Please note that the PET scan must include serum glucose testing prior to scanning

and the timing and scheduling of the scan must fall within protocol guidelines.

In addition, if the first FDG-PET/CT scan is completed prior to registration as noted

above, the participant may undergo a volumetric CT scan after consent and registration to

the trial is complete. Volumetric CT scans are optional at each FDG-PET/CT time point

for each group, but are strongly encouraged. If a participant agrees to undergo volumetric

CT scanning, then two (2) scans must be completed for inclusion of these imaging data in

the study analysis. In Group B, at least one (1) of these two (2) scans must be obtained

before treatment. Test-retest volumetric CT scans do not need to be completed on the

same days as the FDG-PET/CT scans, but do need to be completed within specified time

frames between scans and prior to treatment initiation. For Groups A and C, the first

volumetric CT should be completed at least 24 hours before Imaging Visits A2 or C2. For

Group B, the first volumetric CT must be completed within 7 days before treatment start.

ACRIN 6685:

4. Management of Protocol Imaging Performed Off-schedule - NA

Describe the evaluation, handling and usage of imaging performed according to the Procedure below but not within the “on-schedule” timing window described in Section 1.2.

(e.g. For what purpose(s) may such imaging be used (for clinical decision-making; for data

analysis; for primary endpoints; for secondary endpoints; for continued subject eligibility

evaluation; to supplement but not replace on-schedule imaging, etc.)?

What characteristics or timing will make the imaging acceptable for the purpose?

Is there normalization that should be done to account for the schedule deviation?

What is the expected statistical impact of such imaging on data analysis?

How should such imaging be recorded, archived, etc.)

5. Management of Protocol Imaging Performed Off-specification – NA

Describe the evaluation, handling and usage of imaging described below but not performed completely according to the specified Procedure. This may include deviations or errors in subject preparation, the acquisition protocol, data reconstruction, analysis, interpretation, and/or adequate recording and archiving of necessary data.

(e.g. For what purpose(s) may such imaging be used (for clinical decision-making; for data

analysis; for primary endpoints; for secondary endpoints; for continued subject eligibility

evaluation; to supplement but not replace on-schedule imaging, etc.)?

What characteristics or timing will make the imaging acceptable for the purpose?

Is there normalization that should be done to account for the schedule deviation?

What is the expected statistical impact of such imaging on data analysis?

How should such imaging be recorded, archived, etc.)

ACRIN 6671:

The following statement applies to PET/CT performed either pre-enrollment or after enrollment but pre-treatment. There is no set criteria that requires the original institution to repeat a PET/CT study. However, considering that PET/CT is standard of care for initial staging of cervical and endometrial cancers, the study may be repeated if it is judged by the original institution that the study is suboptimal and does not provide clinical information to stage the patient prior to therapy.(11/16/09) The most common reasons that result in a suboptimal study can be found in Form C1.

6. Management of Off-protocol Imaging – NA

Describe the evaluation, handling and usage of additional imaging not described below. This may include imaging obtained in the course of clinical care or potentially for research purposes unrelated to the clinical trial at the local site.

(e.g. For what purpose(s) may such imaging be used (for clinical decision-making; for data

analysis; for primary endpoints; for secondary endpoints; for continued subject eligibility

evaluation; to supplement but not replace on-schedule imaging, etc.)?

What characteristics or timing will make the imaging acceptable for the purpose?

Is there normalization that should be done to account for the schedule deviation?

What is the expected statistical impact of such imaging on data analysis?

How should such imaging be recorded, archived, etc.)

7. Subject Selection Criteria Related to Imaging

1. Relative Contraindications and Remediations

Describe criteria that may require modification of the imaging protocol.

(e.g. subjects with kidney insufficiency are contraindicated for Contrast CT in this protocol, at the physicians discretion, kidney function may be re-evaluated prior to imaging to see if the insufficiency has resolved, or the subject may be evaluated for dialysis, etc.)

2. Absolute Contraindications and Alternatives

Describe criteria that may fully disqualify the subject for the imaging protocol.

If possible, identify possible alternative imaging protocols.

(e.g. subjects with pacemakers are disqualified for this MRI protocol. Consider using CT protocol UPICT-31254 instead)

These alternatives may also be useful for relative contraindications if remediations described in 1.7.1 are not possible or successful.

If plasma glucose level is ≥7 mmol/l (or >120 mg/dl) the FDG PET study must be rescheduled or the patient excluded depending on the patient circumstances and the trial being conducted.

If blood glucose level is greater than 11 mmol/L, the patient must be rescheduled.

The blood glucose level must be checked before FDG administration to ensure it is below the protocol-specified limit. Patients whose serum glucose concentration exceeds the limit should be rescheduled, and adjustments to diet and medications made if necessary, so that the fasting blood glucose concentration can be brought down to the acceptable range at the time of FDG injection.

ACRIN 6671:

Patients who are pregnant or lactating or who suspect they might be pregnant.

Patients with poorly controlled, insulin-dependent diabetes (fasting blood glucose level >200 mg/dL).

Patients weighing greater than 300 lbs, which is the limit for current PET/CT scanners.

Patients with a history of anaphylactic or life-threatening allergic reactions to any contrast media.

ACRIN 6678: Minimum Acceptable Tumor FDG Uptake. If the FDG uptake of the tumor tissue is too low for quantitative analysis (SUV < 4.0), the participant will be removed from

participation and replaced with another eligible study participant.

ACRIN 6685:

3. Imaging-specific Inclusion Criteria

Describe inclusion criteria that are specifically related to the imaging portion of the study.

ACRIN 6665:

ACRIN 6671: Participants of child-bearing potential must have a negative urine or serum pregnancy test result within 7 days prior to undergoing PET/CT. In addition, they would undergo a urine test on the day of PET/CT examination. The urine test at the institution should detect hCG at the sensitivity of 25 mIU/mL. If the urine test does not have the required sensitivity, a negative serum test is required. Postmenopausal women must have been amenorrheic for at least 12 consecutive months to be considered not to be of child-bearing potential.

ACRIN 6678:

ACRIN 6685:.

2. Site Selection, Qualification and Training

1. Personnel Qualifications –Not specified

1. Technical

2. Physics

3. Physician

PET and PET-CT scans will be evaluated visually directly from a computer screen by a trained Nuclear Medicine Physician -

4. Other (e.g., radiochemistry, radiobiologist, pharmacist, etc.)

2. Imaging Equipment – Not specified ?

All references mention PET or PET-CT systems

Design of clinical PET/CT instrumentation has stabilized in the last 5 years

(Kelloff et al., 2005), such that the efficiencies and resolutions of most PET

instruments are similar.

Patient scans must be conducted on scanners that have been qualified by the ACRIN PET Core Laboratory per the instructions posted on the ACRIN Web site at: corelabs/pet (See Section 12 and Appendix D for detail)

ACRIN 6665:

PET images obtained with dedicated NaI-detector scanners were permitted prior to Amendment 4 (10/28/04) of the study; however, to optimize the quality of PET images in the remaining patients to be accrued, scans obtained with NaI scanners are no longer permitted.

FDG-PET imaging will be performed using "state-of-the-art" equipment (either a dedicated BGO, LSO or GSO full ring PET system), which will have a field of view appropriate for body imaging (≥ 10 cm), high resolution (FWHM ≤ 6.0 mm), high sensitivity, and post-injection transmission capability.

ACRIN 6671:

The PET/CT unit should have a multi-slice CT (>1 slice) and BGO (Bismuth Germinate Oxide), LSO (Lutetium Oxyorthosilicate) or GSO only. Sodium Iodide (NaI) based scanners are not acceptable. The ability to calculate standardized uptake value (SUV) is also mandatory. The PET/CT scanner needs to be qualified by ACRIN before participating in this protocol.

ACRIN 6678:

All FDG-PET/CT and volumetric CT scans will be performed on equipment specifically

qualified for this trial using the same image acquisition parameters as described in

Appendices. All FDG-PET/CT and CT scans for an individual participant will be performed on the same scanner throughout the trial. In the rare instance of equipment malfunction, follow-up scans on an individual participant can be performed on the same type of platform provided that it has been qualified for use in ACRIN 6678 protocol.

List required equipment and software packages, such as CT scanners, image processing workstations, and analysis packages. Specific capabilities of the equipment are described in later sections of this document.

Consider discussing the trade-off between accrual rates and the “bullseye rings of compliance” described in Section 7.2.

3. Infrastructure – Not specified

List required infrastructure, such as subject management capabilities, internet capability, image de-identification and transmission capability.

4. Quality Control (note: inherent in site selection)

1. Procedures

See 12.1.1.

2. Baseline Metrics Submitted Prior to Subject Accrual

See 12.1.2.

ACRIN 6678:

I. Materials Required

Submit the following for each scanner to be used in ACRIN research:

1. Two test patient studies

2. Uniform phantom images (DICOM) with the SUV measurement

3. PET qualification application available at: petcorelab.html

II. Test Patient Image Requirements

Submit images of two unidentified patients consisting of three volume or multi-slice files as

follows:

1. Whole body (torso) transmission (or CT from PET/CT scanner).

2. Whole body (torso) emission with attenuation correction (A/C).

3. Whole body (torso) emission without A/C. (Note that the whole-body transmission images

will represent the reconstructed attenuation information that was used to apply attenuation

correction.)

III. Uniform Phantom Scan Requirements

A. For Water-filled Uniform Phantoms: Fill the phantom with water and inject a known

amount of F-18 (either as fluoride or FDG) into the phantom. The activity injected should be

determined by measurement of the syringe before and after the injection in a properly calibrated

dose calibrator. The injected activity should be chosen to result in an activity concentration

similar to that encountered in clinical FDG imaging, i.e., 1 to 1.5 mCi of F-18 should be added to the 6,283 mL phantom, 2 mCi for the 9,293 mL phantom.

Thoroughly combine the mixture and then scan the phantom with the same protocol used for

patient imaging. Reconstruct the images with the same algorithm and filters used for patient

imaging. Draw a circular or elliptical region of interest (ROI) covering most of the phantom’s

interior over all slices. Measure and report the average SUV and standard deviation in the PET

Instrument Technical Specification form. The expected SUV for the uniform phantom is 1.0

and the acceptable range is 0.9 to 1.1

B. For Ge-68/Ga-68 Calibration Phantoms: Scan the phantom with the same protocol

used for patient imaging. Report the assay date and activity from the calibration certificate of

this phantom on the PET Instrument Technical Specification form. Reconstruct the images with

the same algorithm and filters used for patient imaging. Draw a circular or elliptical region of

interest (ROI) covering most of the interior of the phantom over all slices. Measure and report

the average SUV and standard on the PET Instrument Technical Specification form. The

expected SUV for the uniform phantom is 1.0 and the acceptable range is 0.9 to 1.1.

IV. Image Transmission

Submit test studies and uniform phantom images in DICOM format to ACRIN’s Imaging Core

Lab on Magneto-Optical Disk (MOD), Compact Disc (CD) or via the internet – File Transfer

Protocol (FTP).

3. Metrics Submitted Periodically During the Trial

See 12.1.3.

Additional task-specific Quality Control is described in sections below.

5. Protocol-specific Training

1. Physician

See 10.5, …

2. Physics

See …

3. Technician

See …

3. Subject Scheduling

Describe requirements and considerations for the physician when scheduling imaging and other activities, which may include things both related and unrelated to the trial.

1. Timing Relative to Index Intervention Activity

ACRIN 6678:

Number and Timing of FDG-PET/CT Scans

Eligible participants for the study Groups A and B will generally need to undergo at least

2 cycles of first-line chemotherapy. Eligible participants for Group C will be recruited

regardless of intended therapy. All participants in Group A will undergo three (3) FDG-

PET/CT studies; participants in Group B will undergo two (2) FDG-PET/CTs and may

undergo an optional third FDG-PET/CT; participants in Group C will undergo two (2)

FDG-PET/CT studies.

Participants in Group A will undergo a total of three FDG-PET/CT scans: two pre-

chemotherapy FDG-PET/CT scans (the second pre-chemotherapy FDG-PET/CT scan can

be performed on the day of treatment, but must be done prior to administration of pre-

medication or chemotherapy to exclude acute drug effects on tumor FDG uptake and

FDG biodistribution) and another FDG-PET/CT scan post-cycle 1 of chemotherapy (on

days 19, 20, 21, or 22 before the start of chemotherapy cycle 2).

Participants in Group B will undergo a total of two FDG-PET/CT scans: one pre-

chemotherapy and one post-cycle 1 of chemotherapy (on days 19, 20, 21, or 22 before the

start of chemotherapy cycle 2). An optional third FDG-PET/CT may be completed for

participants post-cycle 2 of chemotherapy (on days 19, 20, 21, or 22 before the start of

chemotherapy cycle 3).

NOTE: Days are listed based on a 21-day chemotherapy cycle; assume first day of

chemotherapy = day 1. Note also that if the beginnning of chemotherapy cycle 2 or cycle

3 is to be delayed (e.g., because of hematologic toxicity from the prior cycle), the FDG-

PET/CT scan still must be obtained on day 19, 20, 21, or 22 of the prior cycle. Details of

the acquisition and analysis of the FDG-PET/CT scans are described in Appendices VI

and VII, and an overview is provided in Section 10.

Participants in Group C will undergo a total of two pre-chemotherapy FDG-PET/CT

scans. The two pre-chemotherapy FDG-PET/CT scans will be performed at least 24

hours apart, but no longer than seven (7) days between scans. Subsequent treatment for

NSCLC is not mandated for this trial group.

Timing Scenario Guidance for Test-Retest FDG-PET/CT and Optional Volumetric

CT Scans (Groups A and C Only)

The following provides clarifying guidance and examples of possible timing scenarios to

accommodate the test-retest scan requests for Groups A and C. They are not all inclusive,

but provide some potential scenarios to aid in completion of the test-retest component of

the trial. Note that all volumetric CT scans are optional. Two volumetric CT scans need

to be completed for inclusion of these imaging data in the study analysis.

Guidance A: The test-retest FDG-PET/CT and volumetric CT scans do not need to be

completed within the same 7-day window—there can be no more than 7 days between

the FDG-PET/CT scans and no more than 7 days between the optional volumetric CT

scans—but all do need to be completed within a 14-day timeframe prior to any cancer

treatment.

Guidance B: If the participant is able, all four scans (two FDG-PET/CT scans within 7

days of each other and two volumetric CT scans within 7 days of each other—see NOTE

below) can be completed on separate days.

Guidance C: If no treatment is planned for Group C, all scans still need to be completed

within a 14-day timeline.

Guidance D—Example Timeline: In the event that a pre-registration scan is acceptable

for the A1 or C1 FDG-PET/CT scan, the first volumetric CT scan can be completed the

same day as the A2 or C2 FDG-PET/CT scan. The second volumetric CT scan could then

be completed at any time within the following 7 days, still prior to any treatment

initiation—or even the same day of treatment initiation as long as it is completed prior to

treatment initiation.

2. Timing Relative to confounding Activities (to minimize “impact”)

(e.g. Avoid scheduling a biopsy on a tumor within X days prior to the FDG-PET scan to evaluate tumor viability; Avoid scheduling the MRI scan within X hours following administration of TPA (for stroke) to the subject.)

3. Scheduling Ancillary Testing

(e.g. order a blood draw to occur within X hours preceding the imaging procedure.)

ACRIN 6678:

Registration Visit (≤ 28 Days Before the Start of Chemotherapy)

Obtain a medical history;

Review clinical laboratory tests completed within 4 weeks of registration to document that

there are no contraindications to beginning the planned chemotherapy regimen (Groups A

and B only; this measure is not necessary for Group C participants);

Perform a physical examination if one has not been performed in the last 6 weeks per

inclusion criteria;

Perform a serum pregnancy test, if applicable;

Obtain pathology reports to confirm the histopathologic diagnosis and stage of NSCLC;

Confirm that participant is fit for the chemotherapy regimen (Groups A and B only);

4. Subject Preparation

1. Prior to Arrival

Describe the presence/absence/timing of subject activities that may impact the procedure or results. These items should typically result in instructions for the subject at time of scheduling, or reminders sent to the subject shortly prior to imaging.

(e.g. oral and/or IV intake, vigorous physical activity, non-protocol-related medical interventions, etc.)

The main purpose of the patient preparation is the reduction of tracer uptake in normal tissue (kidneys, bladder, skeletal muscle, myocardium, brown fat) while maintaining and

optimizing tracer uptake in the target structures (tumour tissue). In the following, a generally applicable protocol is outlined:

- Patients are not allowed to consume any food or sugar for at least 6 h prior to the start of the PET study (i.e. with respect to time of injection of FDG). In practice, this means that patients scheduled to undergo the PET study in the morning should not eat after midnight and preferably have a light meal (no alcohol) during the evening prior to the PET study. Those scheduled for an afternoon PET study may have a light breakfast before

8.00 a.m. (i.e. up to two sandwiches, no sugars or sugar containing sandwich filling). Medication can be taken as prescribed.

- Adequate pre-hydration is important to ensure a sufficiently low FDG concentration of FDG in urine (less artefacts) and for radiation safety reasons (for example, 1 l of water in the 2 h prior to injection; where necessary, account for volume of water in oral contrast

medium for a diagnostic CT scan).

- Parental nutrition and intravenous fluids containing glucose should be discontinued at least 4 h before the PET/CT examination. In addition, the infusion used to administer intravenous pre-hydration must not contain any glucose.

- During the injection of FDG and the subsequent uptake phase the patient should remain seated or recumbent and silent to minimise FDG uptake in muscles. For a brain examination with FDG, injection should take place in a darkened and quiet room and the patient should stay there for the subsequent uptake phase to avoid areas of enhanced uptake due to brain activation. The patient should be kept warm starting at 30–60 min

before the injection of FDG and throughout the following uptake period and PET examination to minimise FDG accumulation in the brown fat (especially relevant if the room is air conditioned). Moreover, all patients must avoid (extreme) exercise for at least

6 h before the PET study (for example, they must not cycle to the hospital).

- In case of pregnancy: see the Society of Nuclear Medicine Procedure Guidelines for General Imaging Version 3 or national guidelines.

Patients should have fasted [except water] for at least 4 h and preferably 6 h before administration of FDG.

Ample hydration is recommended by [oral] intake of 1 L of water during 2 h prior to administration of FDG. In case of venous hydration, no glucose may be present in the infusate.

After administration of FDG, patients should drink 0.5L water before the PET examination. When necessary, 0.5L water or saline can be given intraveneously.

No or minimal exercise 4 h prior to FDG administration ................
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